Schizophrenia is a severe mental disorder that affects about 1% of the population. The etiology of schizophrenia is complex and involves genetic and environmental factors. Schizophrenia is often described in terms of positive, negative and cognitive symptoms. Positive symptoms, such as delusions and hallucinations, are not normally experienced by most individuals. Negative symptoms are deficits of normal emotional responses or of thought processes and cognitive symptoms are cognitive malfunctions. Negative and cognitive symptoms respond less well to medication than positive symptoms, and are contributing more to poor quality of life, functional disability, and the burden on others than do positive symptoms.
Antipsychotics remain the current standard of care for mental disorders including schizophrenia and bipolar mania. The first generation of antipsychotics (typical) such as haloperidol, inhibit dopamine D2 receptors and are moderately effective in treating positive symptoms of schizophrenia, but may cause extrapyramidal movement disorders. Second-generation (atypical) antipsychotics inhibit D2 receptors in conjunction with other receptors (notably 5-hydroxytryptamine 2A (5-HT2A) receptors). Atypical antipsychotics have proved less likely to cause movement disorders, but are associated with weight gain, prolactin and glucose elevation, and sedation. Recent data indicate that agents that target metabolic glutamate receptors (mGluRs) could represent a promising new class of antipsychotics, and such agents are now being developed by several companies. Nevertheless, a large trial known as CATIE, sponsored by the US National Institutes of Health, found that 74% of patients discontinue use within 18 months of therapy due to either poor tolerability or incomplete efficacy, indicating a need for novel therapies.
Kisspeptins (formerly known as Metastins), the products of the Kiss1 gene, bind to a G protein-coupled receptor known as GPR54. Kiss1 was originally identified as a human metastasis suppressor gene. The kisspeptin-GPR54 signaling cascade was recognized several years ago as having a fundamental role in the regulation of sex hormones, and is considered to be the gatekeeper of puberty. Moreover, recent studies indicated that kisspeptin serves additional physiological functions in the cardiovascular system, angiogenesis, and in energy balance. In the hippocampus, kisspeptin enhances excitability of granule cells of the dentate gyrus and secretion of the growth factor brain-derived neurotrophic factor (BDNF, Arai and Orwig, 2008). BDNF has important functions in the development of the nervous system and in brain plasticity-related processes such as memory, learning, and drug addiction. Various studies have shown possible links between BDNF and conditions such as depression, schizophrenia, obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease, Rett syndrome, and dementia, as well as anorexia nervosa and bulimia nervosa.
WO 2010/137022 of the same applicant discloses an elevation in mRNA expression of Kiss1 during adolescence (8 weeks) in the hippocampus of naïve mice. Moreover, the regulation of Kiss1 expression in the hippocampus, unlike its expression in the hypothalamus, is immune-dependent. Thus, functional relationships between the presence of immune deficiency (SCID mice), abnormal expression of kisspeptin in the hippocampus at puberty, and impaired processing of information was found (as measured by prepulse inhibition (PPI)) in these mice (Cardon et al., 2010). PPI is the phenomenon by which a low-intensity prepulse stimulus attenuates the response to a subsequent startle-eliciting noise. Deviations in PPI are commonly associated with the pathophysiology of schizophrenia (Braff and Geyer, 1990) yet abnormal PPI was also found in other psychological disorders (Castellanos et al., 1996; Ornitz et al., 1992; Perry et al., 2007; Swerdlow et al., 1993; Swerdlow et al., 1995).
WO 2010/137022 also discloses that administration of the kisspeptin derived peptide Kp-10 (YNWNSFGLRF-NH2) to SCID mice that have impaired PPI response and to several schizophrenia mouse models, improved PPI response levels. It is additionally disclosed that Kp-10 has a potential anti-depressive activity by a tail suspension test and that Kp-10 improves spatial learning and memory in a water maze in several mouse models, indicating its contribution to broad aspects of cognitive functions such as learning and memory.